Usf1 (Upstream stimulatory factor 1) is a helix-loop-helix leucine zipper family transcription factor1 which in early reports was demonstrated to be part of the general transcription machinery of the cell2, 3. The role of Usf1 in lipid metabolism was established in our laboratory when we first identified region 1q21-23 to be linked to familial combined hyperlipidemia (FCHL) in Finnish families4, and then pinpointed Usf1 to be the causative gene5. The clinical relevance of Usf1 in humans has further been established for coronary atherosclerosis6, 7, acute cardiovascular events8, metabolic derangements9, and all-cause mortality8. Whether the effects of Usf1 protein are beneficial or detrimental to metabolic health, and which biological processes are regulated by Usf1 has yet remained elusive.
WO2005077974 discloses SNPs of Usf1 associated with hyperlipidemia, dyslipidemia and defective carbohydrate metabolism. The publication also suggests inhibitors specific for Usf1 for treatment of hyperlipidemias and/or dyslipidemias including familial combined hyperlipidemia (FCHL), hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, hyperapobetaliporoteinemia, familial dyslipidemic hypertension (FDH), metabolic syndrome, type 2 diabetes mellitus, coronary heart disease, atherosclerosis or hypertension. The publication however, does not indicate how inhibitors could be used for same purpose and the publication does not disclose what the mode of action could be.
Laurila et al 2011 disclosed a congenic strain of Usf1 knockout mice showing lower plasma total VLDL TG as compared to wild type mice. The knockout mice were shown to have increased lipolysis due to higher activity of post-heparin plasma lipoprotein lipase.
Accordingly, even if there are some indications of activation or inhibition of Usf1 for treatment of hyper- and dyslipidemias, the mode of action has not been solved and accordingly no practical solutions have not been provided.